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# Chapter 1 Contents

Chapter 1. Introduction

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1.1. Legislative Requirements

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1.2. History of Reviews of the NAAQS for Lead

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1.3. ISA Development

________________________________ ________________________________ ___________ 1

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Figure 1

- 1. Identification of studies for inclusion in the ISA.

_______________ 1

- 10

1.4. Document Organization

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1.5. Document Scope

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1.6. EPA Framework for Causal Determination

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1.6.1. Scientific Evidence Used in Establishing Causality

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1.6.2. Association and Causation

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1.6.3. Evaluating Evidence for Inferring Causation

________________________________ _____________ 1

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1.6.4. Application of Framework for Causal Determination

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Table 1

- 1. Aspects to aid in judging causality

___________________________ 1

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1.6.5. Determination of Causality

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Table 1

- 2. Weight of evidence for causal determination

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1.6.5.1. Effects on Human Populations

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1.6.5.2. Effects on Ecosystems or Public Welfare

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1.6.6. Concepts in Evaluating Adversity of Health Effects

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1.7. Summary

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Chapter 1 Referenc es

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# Chapter 1. Introduction

Th is first external review draft Integrated Science Assessment (ISA) is a concise review, 

### 1

synthesis, and evaluation of the most policy

- relevant evidence, and communicates critical science 

### 2

judgments relevant to the National Ambient Air Quality Standards (NAAQS) review. As such, the 

### 3

ISA for ms the scientific foundation for the review of the primary (health

- based) and secondary 

### 4

(welfare

- based) NAAQS for lead (Pb). The ISA accurately reflects “ the latest scientific knowledge 

### 5

useful in indicating the kind and extent of identifiable effects on pu blic health which may be 

### 6

expected from the presence of [a] pollutant in ambient air ” (42 U.S.C. 7408). Key information and 

### 7

judgments formerly contained in an Air Quality Criteria Document (AQCD) for Pb are incorporated 

### 8

in this assessment. This ISA thus ser ves to update and revise the evaluation of the scientific evidence 

### 9

available at the time of the previous review of the NAAQS for Pb that was concluded in 2008. 

### 10

The draft Integrated Review Plan for the National Ambient Air Quality Standards for Lead 

### 11

( U.S. EPA, 2011 ) identifies a series of policy

- rel evant questions that provide a framework for this 

### 12

assessment of the scientific evidence. These questions frame the entire review of the NAAQS for Pb, 

### 13

and thus are informed by both science and policy considerations. The ISA organizes, presents, and 

### 14

integrat es the scientific evidence which is considered along with findings from any risk analyses and 

### 15

policy considerations to help the U.S. Environmental Protection Agency (EPA) address these 

### 16

questions during the NAAQS review for Pb. In evaluating the health evid ence, the focus of this 

### 17

assessment is on scientific evidence that is most relevant to the following questions taken directly 

### 18

from the Integrated Review Plan: 

### 19

 What new evidence is available on exposure to Pb through air

- related pathways? Can air



### 20

related pat hways be disentangled from water

- and soil

- related pathways using available 

### 21

data? 

### 22

 What new evidence is available regarding observational studies of Pb exposure? How do 

### 23

these studies inform the assessment of exposure to air

- related pathways? 

### 24

 What new eviden ce is available on biological and other factors that could affect the 

### 25

distribution and accumulation of Pb into blood and bone (e.g., age, diet, gender, race)? 

### 26

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and Environmental Research Online) at http://epa.gov/hero . HERO is a database of scientific literature used by U.S. EPA in the process of developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS)

.May 20 11 1

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– DO NOT CITE OR QUOTE  How and to what extent does previous or concurrent Pb exposure, including duration 

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(e.g., acute, subchronic, chronic) and pattern (e.g., continuous low, extreme peak) impact 

### 2

blood and bone Pb? 

### 3

 What new evidence is available on the relationship between air Pb and blood Pb levels 

### 4

and uncertainties in that relationship? What new knowledge exists regarding the 

### 5

characterization of changes in this relationship when accounting for the multiple 

### 6

pathways of Pb exposure and body burden associated with Pb exposure? What does the 

### 7

current evidence indicate regarding variation in the relationship with variat ion in blood 

### 8

Pb levels or air Pb levels? 

### 9

 To what extent does new scientific evidence increase our understanding of the 

### 10

contributions of Pb from different sources and exposure pathways to blood Pb levels or 

### 11

to other indicators of Pb body burden (e.g., contr ibutions from various air

- related 

### 12

pathways, including diet and indoor dust pathways)? 

### 13

 How do results of recent epidemiologic studies and current or new interpretations of 

### 14

previous findings expand our understanding of the relationship between body burdens o f 

### 15

Pb and neurological effects in children and adults, including deficits in IQ, behavior, 

### 16

learning, and motor skills, as well as risk of neurodegenerative diseases? What new 

### 17

evidence is available on the potential clinical relevance of these effects? Do rec ent 

### 18

studies expand the current understanding of concentration

- response relationships 

### 19

pertinent to the range of Pb exposures currently experienced by the U.S. population? 

### 20

 For what Pb

- induced health effects, is there sufficient evidence in multiple species t o 

### 21

support a quantitative comparison of exposures that induce the effects? 

### 22

 To what extent are the health effects observed in epidemiological studies attributable to 

### 23

exposure to Pb rather than co

- exposures to other toxic metals or environmental 

### 24

contaminants? 

### 25

 In epidemiologic studies, what are the uncertainties in Pb effect estimates due to 

### 26

potential confounding factors (e.g., demographic and lifestyle attributes, socioeconomic 

### 27

status [SES], genetic susceptibility factors, occupational exposure, and access to medical 

### 28

care)? 

### 29

 Based on the new body of evidence, what uncertainties remain regarding the nature and 

### 30

shape of concentration

- response relationships (e.g., threshold, linear, nonlinear)? What 

### 31

evidence is newly available on the uncertainties related to other aspects of statistical 

### 32

model specification and how can it be used to assess the influence of these uncertainties 

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– DO NOT CITE OR QUOTE on the results of epidemiolo gic studies? What evidence is available from toxicological 

### 1

studies of dose

- response relationships? 

### 2

 To what extent is key evidence now available regarding mechanisms for neurological 

### 3

effects associated with “ lower ” (<10 μg/dL or < 5 μg/dL) blood Pb levels (e.g., oxidative 

### 4

stress)? What toxicological evidence is available on mechanisms and dose

- response 

### 5

relationships for other health outcomes (e.g., cardiovascular, renal, or immunological 

### 6

effects), and is there coherence between this and epidemiologic findings for these 

### 7

endpoints? 

### 8

 To what extent is key new evidence available that could inform the understanding of 

### 9

populat ions that are particularly susceptible to Pb exposures? What is known about 

### 10

genetic traits, pre

- existing conditions (obesity), or other factors tha t affect susceptibility 

### 11

(sex)? To what extent is the strength of epidemiologic or toxicological evidence driv en 

### 12

by effects observed in populations with increased susceptibility? 

### 13

 To what extent is key evidence now available to inform our understanding of 

### 14

developmental lifestages that are particularly susceptible to Pb exposures? What is 

### 15

known about critical windo ws of exposure for Pb with regard to their impact on 

### 16

concentration

- response relationships and/or effects elicited? 

### 17

 What do the currently available studies indicate regarding the relationship between 

### 18

exposures to Pb and health effects in those with preexist ing di seases (e.g., renal diseases) 

### 19

compared to healthy individuals ? What medical conditions are identified as increasing 

### 20

susceptibility to Pb effects? What is the nature and time

- course of the development of 

### 21

effects in previously healthy persons and in pe rsons with pre

- existing disease (e.g., 

### 22

cardiovascular disease)? What are the pathways and mechanisms through which Pb may 

### 23

be acting for these groups? 

### 24

In evaluating e vidence on welfare effects of Pb , the focus will be on evidence that can help 

### 25

inform these questions from the Integrated Review Plan: 

### 26

 What new information is available about the nature of the effects of Pb on terrestrial 

### 27

ecosystems , especially Pb that is relevant to air

- related pathways? Is there new evidence 

### 28

of effe cts at current ecosystem loa ds? Is there new evidence that, in combination with the 

### 29

previously existing evidence, supports the development of critical loads for terrestrial 

### 30

ecosystems? 

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 Is there new information available for establishing specific exposure levels at which 

### 32

terrestrial e cological receptors are expected to experience effects? 

### 33May 20 11 1

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– DO NOT CITE OR QUOTE  Are there new empirical data or modeling results that would improve our understanding 

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of the movement of Pb in or through terrestrial systems, or would improve our 

### 2

understanding of Pb bioavailability and pathways of exposure for terrestrial organisms? 

### 3

 Is there new evidence that contributes to a better understanding of the nature and 

### 4

magnitude of the potential effects of Pb on terrestrial ecosystem services? 

### 5

 What new information is available about the nature of the effects of Pb on aquatic 

### 6

ecosystems, especially Pb that is relevant to air

- related pathways? Is there new evidence 

### 7

of effects at current ecosystem loads? Is there new evidence that, in combination with the 

### 8

previously existing evidence, suppor ts the definition of critical loads for aquatic 

### 9

ecosystems? 

### 10

 Is there new information available for establishing specific exposure levels at which 

### 11

aquatic ecological receptors are expected to experience effects? 

### 12

 Are there new empirical data or modeling res ults that would improve our understanding 

### 13

of the movement of Pb in or through aquatic systems or would improve our 

### 14

understanding of Pb bioavailability and pathways of exposure for aquatic organisms? 

### 15

 Is there new evidence that contributes to a better unders tanding of the nature and 

### 16

magnitude of the potential effects of Pb on aquatic ecosystem services? 

### 17

This intro ductory chapter (Chapter 1) of the Pb ISA presents: ( 1 ) background information on 

### 18

pertinent Clean Air Act legislative requirements, the air quality criteria and NAAQS review process, 

### 19

and the history of previous Pb NAAQS reviews; ( 2 ) an overview of the ISA development process 

### 20

and an orientation to the general organizational structure and content of this Pb ISA; and ( 3 ) the 

### 21

framework for causal determin ation used to evaluate the causal nature of air pollution

- induced health 

### 22

and environmental effects in NAAQS reviews. 

### 23



# 1.1. Legislative Requirements

Two sections of the Clean Air Act (CAA) govern the establishment and revision of the 

### 24

NAAQS. Section 108 (42 USC § 7 408) directs the Administrator to identify and list certain air 

### 25

pollutants and then issue air quality criteria for those pollutants. The Administrator is to list those air 

### 26

pollutants that in her “judgment, cause or contribute to air pollution which may rea sonably be 

### 27

anticipated to endanger public health and welfare;” “the presence of which in the ambient air results 

### 28

from numerous or diverse mobile or stationary sources;” and “for which....[the Administrator] plans 

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to issue air quality criteria....” Air quality criteria are intended to “accurately reflect the latest 

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or welfare which may be expected from the presence of [a] pollutant in ambient air....” 42 USC 

### 2

§ 7 408(b). Section 109 (42 USC § 7409) directs the Administrator to propose and promulgate 

### 3

“primary” and “secondary” NAAQS for pollutants for which air quality criteria are issued. Section 

### 4

109(b)(1) defines a primary standard as one “the attainment and mainten ance of which in the 

### 5

judgment of the Administrator, based on such criteria and allowing an adequate margin of safety, are 

### 6

requisite to protect the public health.” 1 A secondary standard, as defined in s ection 109(b)(2), must 

### 7

“ specify a level of air quality the attainment and maintenance of which, in the judgment of the 

### 8

Administrator, based on such criteria, is requisite to protect the public welfare from any known or 

### 9

anticipated adverse effects associated with the presence of [ the] pollutant in the ambient air. ” 2 

### 10

The requirement that primary standards include an adequate margin of safety was intended to 

### 11

address uncertainties associated with inconclusive scientific and technical information available at 

### 12

the time of standard setti ng. It was also intended to provide a reasonable degree of protection against 

### 13

hazards that research has not yet identified. See Lead Industries Association v. EPA , 647 F.2d 1130, 

### 14

1154 (D.C. Cir 1980), cert. denied

, 449 U.S. 1042 (1980); American Petroleum Institute v. Costle

, 

### 15

665 F.2d 1176, 1186 (D.C. Cir. 1981), cert. denied , 455 U.S. 1034 (1982); American Farm Bureau v. 

### 16

EPA , 559 F. 3d 512, 533 (D.C. Cir. 2009); Coalition of Battery Recyclers Association v. EPA , 604 F. 

### 17

3d 613, 617

- 18 (D.C. Cir. 2010). Both kinds of uncertainties are components of the risk associated 

### 18

with pollution at levels below those at which human health effects can be said to occur with 

### 19

re asonable scientific certainty. Thus, in selecting primary standards that include an adequate margin 

### 20

of safety, the Administrator is seeking not only to prevent pollution levels that have been 

### 21

demonstrated to be harmful but also to prevent lower pollutant levels that may pose an unacceptable 

### 22

risk of harm, even if the risk is not precisely identified as t o nature or degree. The CAA does not 

### 23

require the Administrator to establish a primary NAAQS at a zero

- risk level or at background 

### 24

concentration levels, see Lead Industries v. EPA , 647 F.2d at 1156 n.51, but rather at a level that 

### 25

reduces risk sufficiently so as to protect public health with an adequate margin of safety. 

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In addressing the requirement for an adequate margin of safety, the EPA considers such factors 

### 27

as the nature and severity of the health effects involved, the size of sensitive population(s) at risk, 

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and the kind and degree of the uncerta inties that must be addressed. The selection of any particular 

### 29

approach to providing an adequate margin of safety is a policy choice left specifically to the 

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1 The legislative history of section 109 indicates that a primary standa rd is to be set at “the maximum p ermissible ambient air level

... which will protect the health of any [sensitive] group of the population, ” and that for this purpose “ reference should be made to a representative sample of persons comprising the sensitive group rather than to a single pers on in such a group ” S. Rep. No. 91

- 1196, 91st Cong., 2d Sess. 10 (1970).

2 Welfare effects as defined in section 302(h) (42 U.S.C. § 7602(h)) include, but are not limited to, “ effects on soils, water, crops, vegetation, man

- made materials, animals, wildlif e, weather, visibility and climate, damage to and deterioration of property, and hazards to transportation, as well as effects on economic values and on personal comfort and well

- being. ”May 20 11 1

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– DO NOT CITE OR QUOTE A dministrator’s judgment. See Lead Industries Assoc iation v. EPA , 647 F.2d at 1161

- 62 ; Whitman v. 

### 1

American Trucking Associations , 531 U.S. 457, 495 (2001)

. 

### 2

In setting primary and secondary standards that are “ requisite ” to protect public health and 

### 3

welfare, respectively, as provided in section 109(b), EPA ’ s task is to establish standards that are 

### 4

neither more nor less stringent than necessary for these purposes. In so doing, EPA may not consider 

### 5

the costs of implementing the standards. See generally

, Whitman v. American Trucking Associations

, 

### 6

531 U.S. 457, 465

- 472, 475

- 76 (2001). Likewise, “[a]ttainability and technological feasibility are not 

### 7

relevant considerations in the promulgation of national ambient air quality standards.” American 

### 8

Petroleum Institute v. Costle , 665 F. 2d at 1185. 

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Section 109(d)(1) re quires that “ not later than December 31, 1980 , and at 5

- year 

### 10

intervals thereafter, the Administrator shall complete a thorough r eview of the criteria 

### 11

published under section 108 and the national ambi ent air quality standards... and shall make such 

### 12

revisions in such criteria and standards and promulgate such new s tandards as may be appropriate.

.. ” 

### 13

Section 109(d)(2) requires that an independe nt scientific review committee “ shall complete a review 

### 14

of the criteria

... and the national primary and secondary ambien t air quality standards

... and shall 

### 15

recommend to the Administrator any new

... standards and revisions of existing criteria and standar ds 

### 16

as may be appropriate...” Since the early 1980 s, this independent review function has been 

### 17

performed by the Clean Air Scientific Advisory Committee (CASAC). 1 

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# 1.2. History of Reviews of the NAAQS for Lead

On October 5, 1978, EPA promulgated primary and secondary NAAQS for Pb under section 

### 19

109 of the Act (43 FR 46246). Both primary and secondary standards were set at a level of 1.5 μg 

### 20

micrograms per cubic meter (μg/m 3 ), measured as Pb in total suspended particles (Pb

- TSP), not to be 

### 21

exceeded by the maximum arithmetic mean concentration averaged over a calendar quarter. This 

### 22

standard was based on the 1977 AQ CD for Pb ( U.S. EPA, 1977 )

. 

### 23

The first r eview of the Pb standards was initiated in the mid

- 1980s. T he scientific assessment 

### 24

for that review is described in the 1986 Lead AQCD ( U.S. EPA, 1986a ) , the associated Addendum 

### 25

( U.S. EPA, 1986b ) , and the 1990 Supplement ( U.S. EPA, 1990a )

. As part of the review, the Agency 

### 26

designed and performed human exposure and health risk analyses ( U.S. EPA, 1989 ) , the results of 

### 27

which were presented in a 1990 Staff Paper ( U.S. EPA, 1990b ) . Based on the sci entific assessment 

### 28

and the human exposure and health risk analyses, the 1990 Staff Paper presented recommendations 

### 29

for consideration by the Administrator ( U.S. EPA, 1990b ) . After consideration of the documents 

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1 Lists of CASAC members and of members of the CASAC Pb Review Panel are available at: http://yosemite.epa.gov/sab/sabproduct.nsf/WebCASAC/CommitteesandMembership?OpenDocumentMay 20 11 1

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– DO NOT CITE OR QUOTE developed during the review and the significantly changed circumstances since Pb was listed in 

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1976, the Agency did not propose any revisions to the 1978 Pb NAAQS. In a parallel effort, the 

### 2

Agency developed the broad, multi

- program, multimedia, integrated U.S. Strategy for Reducing 

### 3

Lead Exposure ( U.S. EPA, 1991 ) . As part of implementing this strategy, the Agency focused efforts 

### 4

primarily on regulatory and remedial clean

- up actions aim ed at reducing Pb exposures from a variety 

### 5

of non

- air sources judged to pose more extensive public health risks to U.S. populations, as well as 

### 6

on actions to reduce Pb emissions to air, such as bringing more areas into compliance with the 

### 7

existing Pb NAAQS ( U.S. EPA, 1991 )

. 

### 8

The most recent review of the Pb air quality criteria and standards was initiated in November, 

### 9

2004 (69 FR 64926 ) and the Agency’s plans for preparation of the AQCD and conduct of the 

### 10

NAAQS review were contained in two documents: Project Work Plan for Revised Air Quality 

### 11

Criteria for Lead ( U.S. EPA, 2005b ) and Plan for Review of the National Ambient Air Quality 

### 12

Standards for Lead ( U.S. EPA, 2006c )

. 1 The schedule for completion of this review was governed by 

### 13

a judicial order in Missouri Coalition for the Environment v. EPA (No. 4:04CV00660 ERW, Sept. 14, 

### 14

2005; amended April 29, 2008 and July 1, 2008), which specified a schedule for the review of 

### 15

duration substantially shorter than five years. 

### 16

The scientific assessment for the review is described in th e 2006 AQCD for Pb ( U.S. EPA, 

### 17

2006a ) , multiple drafts of which received review by CASAC and the public. EPA also conducted 

### 18

human exposure and health risk assessments and a pilot ecological ri sk assessment for the review, 

### 19

after consultation with CASAC and receiving public comment on a draft analysis plan ( U.S. EPA, 

### 20

2006b )

. Drafts of these quantitative assessments were reviewed by CASAC and the public. The pilot 

### 21

ecological risk assessment was released in December 2006 ( ICF, 2006 ) and the final health risk 

### 22

assessment report was relea sed in November 2007 ( U.S. EPA, 2007 ) . The policy assessment based 

### 23

on both of these assessments, air quality analyses and key evidence from the AQCD was p resented in 

### 24

the Staff Paper ( U.S. EPA, 2006d ) , a draft of which also received CASAC and public review. The 

### 25

final Staff Paper presented OAQPS staff’s evaluation of the public health and welfare policy 

### 26

implications of the key studies and scient ific information contained in the AQCD and presented and 

### 27

interpreted results from the quantitative risk/exposure analyses conducted for this review. Based on 

### 28

this evaluation, the Staff Paper presented OAQPS staff recommendations that the Administrator give 

### 29

consideration to substantially revising the primary and secondary standards to a range of levels at or 

### 30

below 0.2 μg/m 3

. 

### 31

Immediately s ubsequent to completion of the Staff Paper, EPA issued an advance notice of 

### 32

proposed rulemaking (ANPR) that was signed by the Administrator on December 5, 2007 (72 FR 

### 33

1 In the current review, these two documents have been combined into an integrated plan (this document).May 20 11 1

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– DO NOT CITE OR QUOTE 71488). 1 CASAC provided advice and recommendations to the Administrator with regard to the Pb 

### 1

NAAQS based on its review of the ANPR and the previously released final Staff Paper and Risk 

### 2

Assessment Report. The proposed decision on revisions to the Pb NAAQS was signed on May 1, 

### 3

2008 and published in the Federal Register on May 20, 2008 (73 FR 29184). In addition to public 

### 4

comments on the proposal received during the public comment period, both written and oral at two 

### 5

public hearings, the CASAC Pb Panel provided advice and recommendations to the Administrator 

### 6

based on its review of the proposal notice. The final decision on revisions to the Pb NAAQS was 

### 7

signed on October 15, 2008 and published in the Federal Regist er on November 12, 2008 (73 FR 

### 8

66964)

. 

### 9

The November 2008 notice described EPA ’ s revisions to the primary and secondary NAAQS 

### 10

for Pb. In consideration of the much

- expanded health effects evidence on neurocognitive effects of 

### 11

Pb in children, EPA substantiall y revised the primary standard from a level of 1.5 μg/ m 3 to a level of 

### 12

0.15 μg/m 3

. EPA ’ s decision on the level for the standard was based on the weight of the scientific 

### 13

evidence and guided by an evidence

- based framework that integrates evidence for relationships 

### 14

between Pb in air and Pb in children ’ s blood and Pb in children ’ s blood and IQ loss. The level of 

### 15

0.15 μg/m 3 was estimated to protect against air Pb

- related IQ loss in the most highly exposed 

### 16

children, those exposed at the level of the standa rd. Results of the quantitative risk assessment were 

### 17

judged supportive of the evidence

- based framework estimates. The averaging time was revised to a 

### 18

rolling 3

- month period with a maximum (not

- to

- be

- exceeded) form, evaluated over a 3

- year period. 

### 19

As compar ed to the previous averaging time of calendar quarter, this revision was considered to be 

### 20

more scientifically appropriate and more health protective. The rolling average gives equal weight to 

### 21

all three

- month periods, and the new calculation method gives eq ual weight to each month within 

### 22

each three

- month period. Further, the rolling average yields 12 three

- month averages each year to be 

### 23

compared to the NAAQS versus four averages in each year for the block calendar quarters pertaining 

### 24

to the previous standard . The indicator of Pb in total suspended particles (Pb

- TSP) was retained, 

### 25

reflecting the evidence that Pb particles of all sizes pose health risks. The secondary standard was 

### 26

revised to be identical in all respects to the revised primary standards. 2 

### 27

Revisi ons to the NAAQS were accompanied by revisions to the data handling procedures, the 

### 28

treatment of exceptional events and the ambient air monitoring and reporting requirements, as well 

### 29

as emissions inventory reporting requirements. 3 O ne aspect of the new dat a handling requirements is 

### 30

1 The ANPR was one of the features of the revised NAAQS review process that EPA instituted in 2006. :In 2009, this component of the process was replaced by reinstatement of the OAQPS policy assessment (previously termed the Staff Paper).

2 The 2008 NAAQS for Pb are specified at 40 CFR 50.16.

3 The 2008 federal regulatory measurement methods for Pb are specified in 40 CFR 50, Appendix G and 40 CFR part 53. Consideration of ambient air measurements with regard to judging attainment of the standards is spec ified in 40 CFR 50, Appendix R. The Pb monitoring network requireme nts are specified in 40 CFR 58, Appendix D, section 4.5. Guidance on the approach for im plementation of the new

standards was described in the Federal Register notices for the proposed and final rules (73 FR 29184; 73 FR 66964).May 20 11 1

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– DO NOT CITE OR QUOTE the allowance for the use of Pb

- PM 10 monitoring for Pb NAAQS attainment purposes in certain 

### 1

limit ed circumstances at non

- source oriented sites. Subsequent to the 2008 rulemaking, additional 

### 2

revisions were made to the monitoring n etwork requirements. 

### 3



# 1.3. ISA Development

EPA announced the initiation of the current periodic review of the air quality criteria for Pb 

### 4

and the Pb NAAQS in April 2010 and issued a call for information from the public (75 FR 20843)

. 

### 5

In addition to the call for information, publications were identified through an ongoing literature 

### 6

search process that includes extensive computer database mining on specific topics in a variety of 

### 7

disciplines . Literature searches were conducted to identify studies published since t he last review, 

### 8

focusing on publications from January 2006 to March 2011. Search strategies were iteratively 

### 9

modified in an effort to optimize the identification of pertinent publications. Additional papers were 

### 10

identified for inclusion in several ways: re view of pre

- publication tables of contents for journals in 

### 11

which relevant papers may be published and independent identification of relevant literature by 

### 12

expert authors and peer reviewers. It is anticipated that further identif ication of studies will occur 

### 13

during the external review process by the public and CASAC. Publications considered for inclusion 

### 14

in the ISA were added to the Health and Environmental Research Online (HERO) database recently 

### 15

developed by EPA ( http://hero.epa.gov ); note that all citations in the ISA are electronically linked to 

### 16

the database. Typically, only information that underwent scientific peer review and was published or 

### 17

accepted for publication was considered. All relev ant epidemiologic, animal toxicological, and 

### 18

ecological and welfare effects studies published since the last review were considered, including 

### 19

those related to exposure

- response relationsh ips, mode(s) of action (MOA), and susceptible 

### 20

populations. Additiona lly, air quality and emissions data, studies on atmospheric chemistry, 

### 21

environmental fate and transport, as well as issues related to Pb toxicokinetics and exposure were 

### 22

considered for inclusion in the document. The process for identifying studies for cons ideration and 

### 23

inclusion in the Pb ISA is provided in Figure 1

- 1. All references that were considered for inclusio n 

### 24

can be found within the HERO website ( http://hero.epa.gov/lead ). This site contains HERO link s to 

### 25

list s of references that are cited in the ISA, as well as those that were considered for inclusion, but 

### 26

not cited in the ISA, with bibliographic information and abstracts. 

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– DO NOT CITE OR QUOTE 

### Figure 1

- 1 . Identification of studies for inclusion in the ISA.

The ISA build s up on the conclusions of the previous review of the air quality criteria for Pb, 

### 1

presented in the 2006 Pb AQCD ( U.S. EPA, 2006a ) , and focus es on peer reviewed literature 

### 2

published thereafter and on any new interpret ations of previous literature. The 2006 Pb AQCD ( U.S. 

### 3

EPA, 2006a ) evaluated literature pu blished through December 2005. In subsequent chapters, the 

### 4

results of recent scientific studies are inte grated with previous findings. Important older studies may 

### 5

be d iscussed in detail to reinforce key concepts and conclusions or if they are open to 

### 6

reinterpre tation in light of newer data. Older studies also are the primary focus in some areas of the 

### 7

document where research efforts have subsided, and these older studie s remain the definitive work s 

### 8

available in the literature. Emphasis is placed on studies that examine effects associated with Pb 

### 9May 20 11 1

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– DO NOT CITE OR QUOTE concentrations relevant to current population and ecosystem exposures, and particularly those 

### 1

pertaining to Pb concentrations c urrently found in ambient air. Other studies are included if they 

### 2

contain unique data, such as a previously unreported effect or MOA for an observed effect, or 

### 3

examine multiple concentrations to elucidate exposure

- response relationships. 

### 4

Discussions in th e ISA primarily focus on scientific evaluations that can inform the key policy 

### 5

questions described in the Integrated Review Plan ( U.S. EPA, 2011 ) . Although emphasis is placed on 

### 6

discussion of health and welfare effects information, other scientific information is also presented 

### 7

and evaluated in orde r to provide a better understanding of the sources of Pb to ambient air, 

### 8

measurement and concentrations of Pb in ambient air, its subsequent fate and transport in the 

### 9

environment, pathways of human and ecological exposure, and toxicokinetic characteristics of Pb in 

### 10

the human body, as well as the measurement of population exposure to Pb. 

### 11

In general, in assessing the scientific quality and relevance of health and environmental effects 

### 12

studies, the following considerations were taken into account when selecti ng studies for inclusion in 

### 13

the ISA. 

### 14

 Are the study populations, subjects, or animal models adequately selected and are they 

### 15

sufficiently well defined to allow for meaningful comparisons between study or exposure 

### 16

groups? 

### 17

 Are the statistical analyses appro priate, properly performed, and properly interpreted? 

### 18

Are likely covariates adequately controlled or taken into account in the study design and 

### 19

statistical analysis? 

### 20

 Are the air quality data, exposure, or dose metrics of adequate quality? 

### 21

 Are the health or welfare effect measurements meaningful and reliable? 

### 22

Studies published since the 2006 Pb AQCD are emphasized; however, evidence from studies 

### 23

described in previous assessment that are needed to characterize the current state of the science as 

### 24

well as ne w interpretations of older evidence is also considered. Among the studies EPA included in 

### 25

the ISA, particular focus is for the following areas: 

### 26

 N ew studies with adequate blood Pb data at the low end of the distribution ( e.g., 

### 27

<10 μg/dL) ; 

### 28

 N ew studies that provide quantitative effect estimates for populations or lifestages and 

### 29

concentrations of interest ; 

### 30

 Lead exposure or effects in susceptible populations and lifestages ; 

### 31

 I ssues related to the potential for confounding of study effects/responses by non

- Pb 

### 32

exposure

- related factors or variables, and to the modification of Pb

- related effects; 

### 33May 20 11 1

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– DO NOT CITE OR QUOTE  T he timing (e.g., across/within specific lifestages) and duration of exposure associa ted 

### 1

with specific responses; 

### 2

 C oncentration

- response relationships for specific Pb

- related effects; 

### 3

 T he interpretation of Pb biomarkers in epidemiological studies; and air

- to

- blood Pb or 

### 4

air

- to

- bone Pb relationships; 

### 5

 S tudies that evaluate Pb as a component of a c omplex mixtures of pollutants. 

### 6

In selecting epidemiologic studies for inclusion in the present assessment, EPA has consider ed 

### 7

studies containing information on : (1) recent or cumulative exposures relevant to current population 

### 8

exposure levels of Pb; (2) health endpoints that repeat or extend findings from earlier assessments as 

### 9

well as those not previously extensively researched; (3) populations and lifestages that are 

### 10

susceptible to Pb exposures; (4) issues related to potential confounding, and modi fication of effects; 

### 11

and/or (5) important methodological issues (e.g., timing and duration of exposure, concentration



### 12

response relationships, interpretation of biomarkers in epidemiological studies, and air

- to

- blood/bone 

### 13

relationships) related to Pb exposu re effects. In selecting the most informative and policy

- relevant 

### 14

epidemiologic studies on which to give particular focus in the Pb ISA, emphasis is placed on those 

### 15

most relevant to standard setting in the United States. Informative studies conducted in ot her 

### 16

countries are discussed, as appropriate ( e.g., studies for which the mean blood Pb level in the 

### 17

population studied is comparable to the current mean blood Pb level in the corresponding U.S. 

### 18

population). 

### 19

In reviewing new studies that evaluated the respo nse of laboratory animals to Pb exposure, 

### 20

focus in on studies that reveal the effects of Pb exposure within the previously identified target 

### 21

biological systems ( e.g., neurological, c ardiovascular, renal, immune). Additionally, particular focus 

### 22

is on those studies that involve doses or blood Pb/bone Pb levels that approximate human doses or 

### 23

blood Pb/bone Pb levels releva nt to current U.S. populations. Studies at higher exposure doses that 

### 24

result in body burdens above what is found in the current U.S. populat ion are included when the 

### 25

study can provide information relevant to potential MOA , information on exposure

- response 

### 26

relationships, or otherwise improve our understandi ng of susceptible populations. Studies of the 

### 27

efficacy of chelation as a treatment for Pb poisoning in humans and laboratory animals are excluded, 

### 28

except where they provide evidence for the reversibility of a given health effect. 

### 29

In selecting informative studies of welfare effects, emphasis is placed on recent studies that: 

### 30

(1) evaluate the oc currence of effects associated with Pb exposure at current ambient concentrations, 

### 31

with a particular focus on ambient concentrations resulting from ambient air Pb; and/or (2) 

### 32

investigate the effects of Pb on ecosystems at any scale . Studies conducted in ge ographical areas 

### 33

outside the U.S. are included in the assessment if they contribute to the general knowledge of the 

### 34May 20 11 1

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– DO NOT CITE OR QUOTE effects of Pb irrespective of species or locality. As in the selection of health

- related scientific studies, 

### 1

welfare

- related studies were se lected that advance our understanding of MOA by which Pb directly 

### 2

affects terrestrial and aquatic biota. These MOAs, as they pertain to Pb exposures of short or longer 

### 3

duration, informs our understanding of indirect effects that Pb may exert more broadly o n ecosystem 

### 4

structure, function and services. Key studies identified for welfare effects are integrated into the 

### 5

discussion to inform our interpretation of the ecological literature and our characterization of 

### 6

uncertainties. 

### 7

The criteria described here pro vide generalized benchmarks to guide the inclusion in the ISA 

### 8

of the highest quality and most policy

- relevant studies

. Of most relevance for evaluation of studies is 

### 9

whether they provide useful qualitative or quantitative information on exposure

- effect or 

### 10

exposure

- response relationships for effects associated with current blood Pb or bone Pb levels likely 

### 11

to be encountered in the U.S. population. Detailed critical analysis of all studies of the effects of Pb 

### 12

on health and welfare, especially in relation to the above considerations, is beyo nd the scope of this 

### 13

document. Since the last AQCD was completed in 2006 , a considerable portion of the current ISA is 

### 14

devoted to summarizing previously available evidence that contributed to the basis for the last 

### 15

rulemaki ng. 

### 16

As discussed previously, studies included in the text of the ISA are those deemed informative 

### 17

to the NA AQS review process (e.g., policy relevant) and of adequate quality. The ISA text, tables 

### 18

and figures highlight and summarize key study details that a re needed to understand and interpret the 

### 19

results of a study. This information, which was described in the text as well as reiterated in the annex 

### 20

tables of previous documents, includes the air quality system (AQS) data; studies of fate and 

### 21

transport in ai r, water, and soil; human exposure and dosimetry studies; blood or tissue Pb levels 

### 22

corresponding to adverse health effects and dose and duration of exposure in toxicological studies; 

### 23

and, effect estimates, study location, population, exposure metric and t ime window, as well as the 

### 24

characteristics of the exposure/dose distribution for epidemiologic studies. In addition, 

### 25

supplementary materials are provided in the form of output from the HERO database. A key function 

### 26

of the HERO output is to document the bas e of evidence containing publications evaluated for the Pb 

### 27

review, including any publications considered but not included in the ISA. This information is 

### 28

presented as links to lists of references in the HERO database, which include bibliographic 

### 29

informatio n and abstracts and can be found at http://hero.epa.gov/lead

. In addition, certain study 

### 30

characteristics of epidemiologic studies, including location, ages investigated, outcomes, and health 

### 31

endpoints, are summarized in tables included in Chapter 5

. 

### 32

In developing the P b ISA, EPA began by reviewing and summarizing the evidence on : (1) 

### 33

atmospheric sciences and exposure; (2) the health effects evidence from in vivo and in vitro animal 

### 34

toxicological and epidemiologic studi es; and (3) the welfare effects of Pb, including ecological 

### 35

effects. In December 2010, EPA held a peer

- review input workshop to obtain review of the scientific 

### 36May 20 11 1

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– DO NOT CITE OR QUOTE content of initial draft mat erials or sections for the ISA. The purpose of the peer

- review input 

### 1

workshop was to ensure that the ISA was up to date and focused on the most policy

- relevant 

### 2

findings, and to assist EPA with integration of evidence within and across disciplines. Subsequently, 

### 3

EPA a ddressed comments from the peer

- review input workshop and completed the initial integration 

### 4

and synthesis of the evidence. 

### 5

The integration of evidence on health or welfare effects involves collaboration between 

### 6

scientists from various disciplines. As described in the section b elow, the ISA or ganization is based 

### 7

on health and welfare effect categories. As an example, an evaluation of health effects evidence 

### 8

would include summaries of findings from epidemiologic and toxicological studies, and integration 

### 9

of the results to draw conclusions based on the causal framew ork described below. Using the causal 

### 10

framework described in Section 1.6, EPA scientists consider aspects such as strength, consistency, 

### 11

coherence and biological plausibility of the evidence, and develop draft causality judgments on the 

### 12

nature of the relat ionships. The draft integrative synthesis sections and conclusions are reviewed by 

### 13

EPA internal experts and, as appropriate, by outside expert authors. In practice, causality 

### 14

determinations often entail an iterative process of review and evaluation of the evidence. The draft 

### 15

ISA is released for review by the CASAC and the public. Comments on the characterization of the 

### 16

science as well as the implementation of the causal framework are carefully considered in revising 

### 17

and completing the ISA. 

### 18



# 1.4. Document Organiza tion

This ISA is composed of seven chapters. This introductory chapter presents background 

### 19

information, and provides an overview of EPA ’ s framework for making causal judgments. Chapter 2 

### 20

is an integrated summary of key findings and c onclusions regarding th e source

- to

- dose paradigm, 

### 21

toxicokinetics, MOA, important health effects of Pb, including neurological, cardiovascular, renal, 

### 22

immunological, reproductive and developmental, and cancer outcomes, and welfare effects of Pb, 

### 23

including terrestrial and aquatic ecosystem impacts. More detailed summaries, evaluations

, and 

### 24

integration of the evidence are included in Chapters 3 through 7 . Chapter 3 highlights key concepts 

### 25

or issues relevant to understanding the sources, ambient concentrations, atmospheric behavior, and 

### 26

fate of Pb in the environment. Chapter 4 summarizes key concepts and recent findings on exposures 

### 27

to Pb using a conceptua l model that reflects the multimedia nature of Pb exposure, toxicokinetics, 

### 28

biomarkers of Pb exposure and body burden, and models. Chapter 5 presents a discussion of the 

### 29

MOA of Pb and evaluates and integrates epidemiologic and animal toxicological informat ion on 

### 30

health effects related to Pb exposures, including neurological, cardiovascular, renal, immunological, 

### 31

reproductive and developmental, and cancer outcomes. Chapter 6 summarizes the evidence on 

### 32May 20 11 1

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– DO NOT CITE OR QUOTE potentially susceptible populations for health effects of Pb exposure. Chapter 7 evaluates welfare 

### 1

effects evidence that is relevant to the review of the secondary NAAQS for Pb, including ecological 

### 2

effects. The chapter also presents key conclusions and scientific judgments regarding cau sality for 

### 3

welfare effect s of Pb

. 

### 4



# 1.5. Document Scope

For the current NAAQS review of the primary Pb standard, relevant scientific information on 

### 5

human exposures and health effects associated with exposure to ambient Pb has been assessed. 

### 6

Previous reviews have included an extensive bo dy of evidence from the major health disciplines of 

### 7

toxicology and epidemiology on the health effects of Pb exposure ( U.S. EPA, 1986a

, 2006a ) . In this 

### 8

review, the conclusions from previous reviews are summarized at the beginning of each health 

### 9

outcome discussion to provide the foundation for consi deration of evidence from recent studies. 

### 10

In some cases where no new information is available, the summary of key findings and conclusions 

### 11

from the previous Pb AQCDs serve as the basis for current key conclusions. Results of key studies 

### 12

from previous revie ws are included in ISA discussions or tables and figures, as appropriate, and 

### 13

conclusions are drawn based on the synthesis of evidence from recent studies with the extensive 

### 14

literature summarized in previous reviews. 

### 15

The review also assesses scientific in formation associated with known or anticipated 

### 16

ecological and public welfare effects that is relevant to the review of the secondary Pb standard. 

### 17

Research on the ecological effects of Pb, including impacts on vegetation, has been discussed 

### 18

extensively in p revious AQCDs. This review incorporates and discusses findings of recent studies, 

### 19

building upon previous evaluations and conclusions. 

### 20



# 1.6. EPA Framework for Causal Determination

The EPA has developed a consistent and transparent basis to evaluate the causal na ture of air 

### 21

pollution

- induced health or environmental effects. The framework described below establishes 

### 22

uniform language concerning causality and brings more specificity to the findings. This standardized 

### 23

language was drawn from across the federal governm ent and wider scientific community, especially 

### 24

from the National Academy of Sciences (NAS) Institute of Medicine (IOM) document, Improving 

### 25

the Presumptive Disability Decision

- Making Process for Veterans

, ( 2008 ) the most recent 

### 26

comprehensive work on evaluating causality. 

### 27May 20 11 1

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– DO NOT CITE OR QUOTE This introductory section focuses on the evaluation of health effects evidence. While focusing 

### 1

on human health outcomes, the concepts are also generally relevant to causality determination for 

### 2

welfare effects. This section: 

### 3

 describes the kinds of scientific evidence used in establishing a general causal 

### 4

relationship between exposure and health effects; 

### 5

 defines causation , in contrast to statistical association; 

### 6

 discusses the sources of evidence necessary to reach a conclusion about t he existence of 

### 7

a causal relationship; 

### 8

 highlights the issue of multifactorial causation; 

### 9

 identifies issues and approaches related to uncertainty; and 

### 10

 provides a framework for classifying and characterizing the weight of evidence in 

### 11

support of a general causal relationship. 

### 12

Approaches to assessing the separate and combined lines of evidence (e.g., epidemiologic, 

### 13

controlled human exposure, and animal toxicologica l studies) have been formulated by a number of 

### 14

regulatory and science agencies, including the IOM of the NAS ( 2008 ) , International Agency for 

### 15

Research on Cancer ( 2006 )

, EPA Guidelines for Carcinogen Risk Assessment ( 2005a ) , Centers for 

### 16

Disease Control and Prevention ( 2004 ) , and National Acid Precipitation Assessment Program ( 1991 )

. 

### 17

These formalized approaches offer guidance for assessing causality. The frameworks are similar in 

### 18

nature, although adapted to different purposes, and have proven effective i n providing a uniform 

### 19

structure and language for causal determinations. Moreover, these frameworks have supported 

### 20

decision

- making under conditions of uncertainty. 

### 21



## 1.6.1. Scientific Evidence Used in Establishing Causality

Causality determinations are based on the evaluation and synthesis of evidence from across 

### 22

scientific disciplines; the type of evidence that is most important for such determinations will vary 

### 23

by assessment. The most direct evidence of a causal relationship between pollutant exposures and 

### 24

human h ealth effects comes from controlled human exposure studies. This type of study 

### 25

experimentally evaluates the health effects of administered exposures in human volunteers under 

### 26

highly

- controlled laboratory conditions. C ontrolled human exposure studies are no t done for Pb, and 

### 27

thus, are unavailable for consideration. 

### 28

In most epidemiologic or observational studies of humans, the investigator does not control 

### 29

exposures or intervene with the study population. Broadly, observational studies can describe 

### 30

associatio ns between exposures and effects. In the case of Pb, most observational studies use 

### 31May 20 11 1

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– DO NOT CITE OR QUOTE biomarkers of Pb (i.e., blood or bone Pb) rather than exposures to relate to effects. These studies fall 

### 1

into several categories: cross

- sectional and longitudinal studies. “ Natural experiments ” offer the 

### 2

opportunity to investigate changes in health with a change in exposure; these include comparisons of 

### 3

health effects before and after a change in population exposures, such as the closure of a pollution 

### 4

source. 

### 5

Experimental a nimal data can help characterize effects of concern, exposure

- response 

### 6

relationships, susceptible populations, MOAs and enhance understanding of biological plausibility of 

### 7

observed effects. In the absence of human data, animal data alone may be sufficient to support a 

### 8

likely causal determination, assuming that similar responses are expected in humans. 

### 9



## 1.6.2. Association and Causation

“Causation” is a significant, effectual relationship between an agent and an effect on health or 

### 10

welfare. “ Association ” is the sta tistical dependence among events, characteristics, or other variables. 

### 11

An association is prima facie evidence for causation; alone, however, it is insufficient proof of a 

### 12

causal relationship between exposure and disease or health effect. Determining whethe r an observed 

### 13

association is causal rather than spurious involves consideration of a number of factors, as described 

### 14

below. Much of the newly available health information evaluated in this ISA comes from 

### 15

epidemiologic studies that report a statistical asso ciation between ambient exposure and health 

### 16

outcomes. 

### 17

Many of the health and environmental outcomes reported in these studies have complex 

### 18

etiologies. Diseases such as asthma, cardiovascular disease , Parkinson ’ s disease or cancer are 

### 19

typically initiated b y a web of multiple agents. Outcomes depend on a variety of factors, such as age, 

### 20

genetic susceptibility, nutritional status, immune competence, and social factors ( Gee & Payne



### 21

Sturges, 2004 ; Sam et & C. C. Bodurow, 2008 ) . Effects on ecosystems are also multifactorial with a 

### 22

complex web of causation. Further, exposure to a combination of agents could cause synerg istic or 

### 23

antagonistic effects. Thus, the observed risk represents the net effect of many actions and 

### 24

counteractions. 

### 25



## 1.6.3. Evaluating Evidence for Inferring Causation

Moving from association to causation involves the elimination of alternative explanations for 

### 26

the association. In estimating the causal influence of an exposure on health or environmental effects, 

### 27

it is recognized that scientific findings incorporate uncertainty. “ Uncertainty ” can be defined as a 

### 28

state of having limited knowledge where it is impos sible to exactly describe an existing state or 

### 29

future outcome, e.g., the lack of knowledge about the correct value for a specific measure or 

### 30

estimate. Uncertainty characterization and uncertainty assessment are two activities that lead to 

### 31May 20 11 1

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– DO NOT CITE OR QUOTE different degrees of sophistication in describing uncertainty. Uncertainty characterization generally 

### 1

involves a qualitative discussion of the thought processes that lead to the selection and rejection of 

### 2

specific data, estimates, scenarios, etc. Uncertainty assessment is more quantitative. The process 

### 3

begins with simpler measures (e.g., ranges) and simpler analytical techniques and progresses, to the 

### 4

extent needed to support the decision for which the assessment is conducted, to more complex 

### 5

measures and techniques. Data w ill not be available for all aspects of an assessment and those data 

### 6

that are available may be of questionable or unknown quality. In these situations, evaluation of 

### 7

uncertainty can include professional judgment or inferences based on analogy with similar situations. 

### 8

The net result is that the assessment will be based on a number of assumptions with varying degrees 

### 9

of uncertainty. Uncertainties commonly encountered in evaluating health evidence for the criteria air 

### 10

pollutants are outlined below for epidemio logic and experimental studies. Various approaches to 

### 11

evaluating uncertainty include classical statistical methods, sensitivity analysis, or probabilistic 

### 12

uncertainty analysis, in order of increasing complexity and data requirements. The ISA generally 

### 13

eval uates uncertainties qualitatively in assessing the evidence from across studies; in some 

### 14

situations, quantitative analysis approaches, such as meta

- regression, may be used. 

### 15

Meta

- analysis may be a valuable tool for evaluating evidence by combining results from a 

### 16

body of studies. Blair et al. ( 1995 ) observe that meta

- analysis can enhance understanding of 

### 17

associations between exposures and effects that are not readily apparent in examination of indi vidual 

### 18

study results and can be particularly useful for formally examining sources of heterogeneity. 

### 19

However, these authors note that meta

- analysis may not be useful when the relationship between the 

### 20

exposure and outcome is obvious, when only a few studies are available for a particular exposure



### 21

outcome relationship, where there is limited access to data of sufficient quality, or where there is 

### 22

substantial variation in study design or population. In addition, important differences in effect 

### 23

estimates, expos ure metrics, or other factors may limit or even preclude quantitative statistical 

### 24

combination of multiple studies. 

### 25

Epidemiologic studies provide important information on the associations between health 

### 26

effects and exposure of human populations to ambient a ir pollution. In the evaluation of 

### 27

epidemiologic evidence, one important consideration is potential confounding. C onfounding is “ ...a 

### 28

confusion of effects. Specifically, the apparent effect of the exposure of interest is distorted because 

### 29

the effect of an ex traneous factor is mistaken for or mixed with the actual exposure effect (which 

### 30

may be null) ” ( Rothman & Greenland, 1998 ) . One ap proach to remove spurious associations from 

### 31

possible confounders is to control for characteristics that may differ between exposed and unexposed 

### 32

persons; this is frequently termed “ adjustment. ” Appropriate statistical adjustment for confounders 

### 33

requires id entifying and measuring all reasonably expected confounders. Deciding which variables 

### 34

to control for in a statistical analysis of the association between exposure and disease or health 

### 35

outcome depends on knowledge about possible mechanisms and the distribu tions of these factors in 

### 36May 20 11 1

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– DO NOT CITE OR QUOTE the population under study. In addition, scientific judgment is needed regarding likely sources and 

### 1

magnitude of confounding, together with consideration of how well the existing constellation of 

### 2

study designs, results, and analys es address this potential threat to inferential validity. 

### 3

Another important consideration in the evaluation of epidemiologic evidence is effect 

### 4

modification

. “ Effect

- measure modification differs from confounding in several ways. The main 

### 5

difference is tha t, whereas confounding is a bias that the investigator hopes to prevent or remove 

### 6

from the effect estimate, effect

- measure modification is a property of the effect under study

... In 

### 7

epidemiologic analysis one tries to eliminate confounding but one tries to detect and estimate effect



### 8

measure modification ” ( Rothman & Greenland, 1998 ) . Examples of effect modifiers in some of the 

### 9

studie s evaluated in this ISA include environmental variables, such as temperature or humidity, 

### 10

individual risk factors, such as education, cigarette smoking status, age in a prospective cohort study, 

### 11

and community factors, such as percent of population >65 y ea r s old. It is often possible to stratify 

### 12

the relationship between health outcome and exposure or biomarker by one or more of these risk 

### 13

factor variables. For variables that modify the association, effect estimates in each stratum will be 

### 14

different from one another and different from the overall estimate, indicating a different exposure



### 15

response relationship may exist in populations represented by these variables. Effect modifiers may 

### 16

be encountered ( 1 ) within single

- city time

- series studies ; or ( 2 ) across ci ties in a two

- stage 

### 17

hierarchical model or meta

- analysis. 

### 18

S everal statistical methods are available to detect and control for potential confounders, with 

### 19

none of them being completely satisfactory. Multivariable regression models constitute one tool for 

### 20

est imating the association between exposure and outcome after adjusting for characteristics of 

### 21

participants that might confound the results. The use of multipollutant regression models has been 

### 22

the prevailing approach for controlling potential confounding by copollutants in air pollution health 

### 23

effects studies. Finding the pollutant likely responsible for the health outcome from multipollutant 

### 24

regression models is made difficult by the possibility that one or more air pollutants may be acting as 

### 25

a surrogate fo r an unmeasured or poorly

- measured pollutant or for a particular mixture of pollutants. 

### 26

In addition, more than one pollutant may exert similar health effects, resulting in independently 

### 27

observed associations for multiple pollutants. Further, the correlatio n between the air pollutant of 

### 28

interest and various copollutants may make it difficult to discern associations between different 

### 29

pollutant exposures and health effects. Thus, results of models that attempt to distinguish gaseous 

### 30

and particle effects must b e interpreted with caution. The number and degree of diversity of 

### 31

covariates, as well as their relevance to the potential confounders, remain matters of scientific 

### 32

judgment. Despite these limitations, the use of multipollutant models is still the prevailin g approach 

### 33

employed in most air pollution epidemiologic studies, and provides some insight into the potential 

### 34

for confounding or interaction among pollutants. 

### 35May 20 11 1

- 20 DRAFT

– DO NOT CITE OR QUOTE Another way to adjust for potential confounding is through stratified analysis, i.e., examining 

### 1

t he association within homogeneous groups with respect to the confounding variable. The use of 

### 2

stratified analyses has an additional benefit: it allows examination of effect modification through 

### 3

comparison of the effect estimates across different groups. If investigators successfully measured 

### 4

characteristics that distort the results, adjustment of these factors help separate a spurious from a true 

### 5

causal association. Appropriate statistical adjustment for confounders requires identifying and 

### 6

measuring all re asonably expected confounders. Deciding which variables to control for in a 

### 7

statistical analysis of the association between exposure and disease or health outcome depends on 

### 8

knowledge about possible mechanisms and the distributions of these factors in the population under 

### 9

study. Identifying these mechanisms makes it possible to control for potential sources that may result 

### 10

in a spurious association. 

### 11

Adjustment for potential confounders can be influenced by differential exposure measurement 

### 12

error. There are several components that contribute to exposure measurement error in epidemiologic 

### 13

studies, including the difference between true and measured ambient concentrations, the difference 

### 14

between average personal exposure to ambient pollutants and ambient concent rations at central 

### 15

monitoring sites, and the use of average population exposure rather than individual exposure 

### 16

estimates. Previous AQCDs have examined the role of measurement error in time

- series 

### 17

epidemiologic studies using simulated data and mathematical analyses and suggested that “ transfer 

### 18

of effects ” would only occur under unusual circumstances (i.e., “ true ” predictors having high 

### 19

positive or negative correlation; substantial measurement error; or extremely negatively correlated 

### 20

measurement errors) ( U.S. EPA, 2004 )

. 

### 21

Confidence that unmeasured confounders are not producing the findings is increased when 

### 22

multiple studies are conducted in various settings using different subjects or exposures; each of 

### 23

which might eliminate another source of confou nding from consideration. Thus, multicity studies 

### 24

which use a consistent method to analyze data from across locations with different levels of 

### 25

covariates can provide insight on potential confounding in associations. Intervention studies, because 

### 26

of their q uasi

- experimental nature, can be particularly useful in characterizing causation. 

### 27

In addition to controlled human exposure and epidemiologic studies, the tools of experimental 

### 28

biology have been valuable for developing insights into human physiology and pa thology. 

### 29

Laboratory tools have been extended to explore the effects of putative toxicants on human health, 

### 30

especially through the study of model systems in other species. These studies evaluate the effects of 

### 31

exposures to a variety of pollutants in a highl y controlled laboratory setting and allow exploration of 

### 32

MOAs or mechanisms by which a pollutant may cause effects. Background knowledge of the 

### 33

biological mechanisms by which an exposure might or might not cause disease can prove crucial in 

### 34

establishing or negating a causal claim. There are, however, uncertainties associated with 

### 35

quantitative extrapolations between laboratory animals and humans on the pathophysiological effects 

### 36May 20 11 1

- 21 DRAFT

– DO NOT CITE OR QUOTE of any pollutant. Animal species can differ from each other in fundamental aspec ts of physiology and 

### 1

anatomy (e.g., metabolism, airway branching, hormonal regulation) that may limit extrapolation. 

### 2

Interpretations of experimental studies of pollutant effects in laboratory animals, as in the case 

### 3

of environmental comparative toxicology studies, are affected by limitations associated with 

### 4

extrapolation models. The differences between humans and rodents with regard to pollutant 

### 5

absorption and distribution profiles based on metabolism, hormonal regulation, exposure dose, and 

### 6

differences in target organ structure and anatomy, all have to be taken into consideration. Also, in 

### 7

spite of a high degree of homology and the existence of a high percentage of orthologous genes 

### 8

across humans and rodents (particularly mice), extrapolation of molecular alterations at the gene 

### 9

level is complicated by species

- specific differences in transcriptional regulation. Given these 

### 10

molecular differences, at this time there are uncertainties associated with quantitative extrapolations 

### 11

between laboratory animals and h umans of observed pollutant

- induced pathophysiological 

### 12

alterations under the control of widely varying biochemical, endocrine, and neuronal factors. 

### 13



## 1.6.4. Application of Framework for Causal Determination

EPA uses a two

- step approach to evaluate the scientific e vidence on health or environmental 

### 14

effects of criteria pollutants. The first step determines the weight of evidence in support of causation 

### 15

and characterizes the strength of any resulting causal classification. The second step includes further 

### 16

evaluation o f the quantitative evidence regarding the concentration

- response relationships and the 

### 17

loads or levels, duration and pattern of exposures at which effects are observed. 

### 18

To aid judgment, various “ aspects ” 1 of causality have been discussed by many philosoph ers 

### 19

and scientists. The most widely cited aspects of causality in epidemiology, and public health, in 

### 20

general, were articulated by Sir Austin Bradford Hill ( 1965 ) and have been widely used ( CDC, 2004 ; 

### 21

IARC, 2006 ; NRC, 2004 ; Samet & C. C. Bodurow, 2008 ; U.S. EPA, 2005a ) . Several adaptations of 

### 22

the Hill aspects have been used in aiding causality judgments in the ecological sciences ( Adams, 

### 23

2003 ; Collier, 2003 ; Fox, 1991 ; Gerritsen et al., 1998 ) . These aspects ( Hill, 1965 ) have been 

### 24

modified (Table 1

- 1) for use in causal determinations specific to health and welfare effects or 

### 25

pollutant exposures. 2 Some aspects are more likely than others to be relevant for evaluating evidence 

### 26

on the health or environmental effects of criteria air pollutants. For example, the analogy aspect does 

### 27

not always apply and specificity would not be expected for multi

- etiologic h ealth outcomes such as 

### 28

asthma or cardiovascular disease, or ecological effects related to acidification. Aspects that usually 

### 29

1 The “aspects” described by Hill ( 1965 ) have become, in the subsequent literature, more commonly described as “criteria.” The original term “aspects” is used here to avoid confusion with ‘cri teria’ as it is used, with different meaning, in the Clean Air Act.

2 The Hill aspects were developed for interpretation of epidemiologic results. They have been modified here for use with a broa der array of data, i.e., epidemiologic, controlled human expo sure, and animal toxicological studies, as well as in vitro data, and to be more consistent with EPA’s Guidelines for Carcinogen Risk Assessment.May 20 11 1

- 22 DRAFT

– DO NOT CITE OR QUOTE play a larger role in determination of causality are consistency of results across studies, coherence of 

### 1

effects observed in diffe rent study types or disciplines, biological plausibility, exposure

- response 

### 2

relationship, and evidence from “ natural ” experiments. 

### 3

Although these aspects provide a framework for assessing the evidence, they do not lend 

### 4

themselves to being considered in ter ms of simple formulas or fixed rules of evidence leading to 

### 5

conclusions about causality ( Hill, 1965 ) . For example, one cannot simply count the number of 

### 6

studies reporting statistically significant results or statistically nonsignificant results and reach 

### 7

credible conclusions about the relative weight of the evidence and t he likelihood of causality. Rather, 

### 8

these important considerations are taken into account with the goal of producing an objective 

### 9

appraisal of the evidence, informed by peer and public comment and advice, which includes 

### 10

weighing alternative views on contro versial issues. In addition, it is important to note that the aspects 

### 11

in Table 1

- 1 cannot be used as a strict checklist, but rather to determine the weight of the evidence 

### 12

for inferring causality. In particular, not meeting one or more of the principles do es not automatically 

### 13

preclude a determination of causality ( CDC, 2004 )

. 

### 14May 20 11 1

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– DO NOT CITE OR QUOTE 

### Table 1

- 1. Aspects to aid in judging causality

Aspect Decription
Consistency of the

observed association An inference of causality is strengthened when a pattern of elevated risks is observed across several independent studies, conducted in multiple locations by multiple investigators. The reproducibility of findings

co nstitutes one of the strongest arguments for causality. If there are discordant results among investigations, possible reasons such as differences in exposure, confounding factors, and the power of the study are

considered.

Coherence An inference of causality from epidemiologic associations may be strengthened by other lines of evidence (e.g., controlled human exposure and animal toxicological studies) that support a cause

- and

- effect interpretation of the association. Causality is also supported when epidemiologic associations are reported across study designs and across related health outcomes. Evidence on ecological or welfare effects may be drawn from a variety of experimental approaches (e.g., greenhouse, laboratory, and field) and subdisciplines of ecology (e.g., community ecology, biogeochemistry and paleological/ historical reconstructions). The coherence of evidence from various fields greatly adds to the strength of an inference of causality. The

absence of other lines of eviden ce, however, is not a reason to reject causality

Biological plausibility An inference of causality tends to be strengthened by consistency with data from experimental studies or other sources demonstrating plausible biological mechanisms. A proposed mechanistic linking between an effect, and exposure to the agent, is an important source of support for causality, especially when data establishing the existence and functioning of those mechanistic links are available. A lack of biological understanding, however, is not a reason to reject causality.

Biological gradient (exposure

- response relationship) A well

- characterized exposure

- response relationship (e.g., increasing effects associated with greater exposure) strongly suggests cause and effect, espec ially when such relationships are also observed for duration of exposure (e.g., increasing effects observed following longer exposure times). There are, however, many possible reasons that a study may fail to detect an exposure

- response relationship. Thus, although the presence of a biological gradient may support causality, the absence of an exposure

- response relationship does not exclude a causal relationship.

Strength of the

observed association The finding of large, precise risks increases confidence that the association is not likely due to chance, bias, or other factors. However, given a truly causal agent, a small magnitude in the effect could follow from a lower level of exposure, a lower potency, or the prevalence of other agents causing similar e ffects. While large effects support causality, modest effects therefore do not preclude it.

Experimental evidence The strongest evidence for causality can be provided when a change in exposure brings about a change in occurrence or frequency of health or welfare effects.

Temporal relationship

of the observed

association Evidence of a temporal sequence between the introduction of an agent and appearance of the effect constitutes another argument in favor of causality.

Specificity of the

observed association As originally intended, this refers to increased inference of causality if one cause is associated with a single

effect or disease ( Hill, 1965 ) . Based on the current understanding this is now considered one of the weaker guidelines for causality; for example, many agents cause respiratory disease and respiratory disease has multiple causes. At the scale of ecosystems, as in epidemiology, complexity is such that single agents causing single effects, and single effects following single causes, are extremely unlikely. The ability to demonstrate specificit y under certain conditions remains, however, a powerful attribute of experimental studies. Thus, although the presence of specificity may support causality, its absence does not exclude it.

Analogy Structure activity relationships and information on the agent ’ s structural analogs can provide insight into whether an association is causal. Similarly, information on mode of action for a chemical, as one of many structural analogs, can inform decisions regarding likely causality.



## 1.6.5. Determination of Causality

I n the ISA, EPA assesses the results of recent relevant publications, building upon evidence 

### 1

available during the previous NAAQS review, to draw conclusions on the causal relationships 

### 2

between relevant exposures or body burden, as measured by blood or tissu e Pb levels

, and health 

### 3May 20 11 1

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– DO NOT CITE OR QUOTE effects and relevant Pb concentrations and environmental effects. This ISA uses a five

- level 

### 1

hierarchy that classifies the weight of evidence for causation, not just association 1 ; that is, whether 

### 2

the weight of scientific evidence m akes causation at least as likely as not, in the judgment of the 

### 3

reviewing group. In developing this hierarchy, EPA has drawn on the work of previous evaluations, 

### 4

most prominently the IOM ’ s Improving the Presumptive Disability Decision

- Making Process for 

### 5

V eterans ( 2008 ) , EPA ’ s Guidelines for Carcinogen Risk Assessment ( 200 5a ) , and the U.S. Surgeon 

### 6

General ’ s smoking reports ( CDC, 2004 ) . In the ISA, EPA uses a series of five descriptors to 

### 7

characterize the weight of evidence for causality. This weight of evidence evaluation is based on 

### 8

various lines of evidence from across the health and environmental effects disciplines. These 

### 9

separate judgments are integrated into a qualitative statement about the overall weight of the 

### 10

evidence and causality. The five descriptors for causal determination are described in Table 1

- 2. 

### 11

For the Pb ISA, determination of causality involved the evaluation of evidence for different 

### 12

types of health effects associated with Pb biomarkers of exposure and body burden (i.e., blood and 

### 13

tissue). In making determinations of causality for Pb, evidence was evaluated for health outcome 

### 14

categories, such as neurological effects, and then conclusions were drawn based upon the integration 

### 15

of evidence from across disciplines (e.g., epide miology and toxicology) and also across the suite of 

### 16

related individual health outcomes. To accomplish this integration, evidence from multiple and 

### 17

various types of studies was considered. Response was evaluated over a range of observations which 

### 18

was deter mined by the type of study and methods of exposure or dose and response measurements. 

### 19

Results from different protocols were compared and contrasted. 

### 20

1 It should be noted that the CDC and IOM frameworks use a four

- category hierarchy for the strength of the evi dence. A five

- level hierarchy is used here to be consistent with the EPA Guidelines for Carcinogen Risk Assessment ( U.S. EPA, 2005a ) and to provide a more nuanced set of categories.May 20 11 1

- 25 DRAFT

– DO NOT CITE OR QUOTE 

### Table 1

- 2

. Weight of evidence for causal determination

Determination Health Effects Ecological and Welfare Effects

Causal relationship Evidence is sufficient to conclude that there is a causal

relation ship with relevant blood or tissue Pb levels. That is,

blood or tissue Pb levels have been shown to result in

health effects in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example: a) controlled human exposure studies that demonstrate consistent effects; or b) observational studies that cannot be explained by plausible alternatives or a re supported by other lines of evidence (e.g., animal studies or mode of action information). Evidence includes replica ted and consistent high

- quality studies by multiple investigators. Evidence is sufficient to conclude that there is a causal

relationshi p with relevant pollutant exposures. That is, the pollutant has been shown to result in effects in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. Controlled exposure studies (laboratory or small

- to medium

- sca le field studies) provide the strongest evidence for causality, but the scope of inference may be limited. Generally, determination is based on multiple studies conducted by multiple research groups, and evidence that is considered sufficient to infer

a ca usal relationship is usually obtained from the joint consideration of many lines of evidence that reinforce

each other.

Likely to be a

causal relationship Evidence is sufficient to conclude that a causal relationship is likely to exist with relevant blood or tissue Pb levels, but important uncertainties remain. That is,

blood or tissue Pb levels have been shown to result in

health effects in studies in which chance and bias can be

ruled out with reasonable confi dence but potential issues remain. For examp le: a) obser vational studies show an
association, but confounding factors are diffi cult to address and/or other lines of evidence (controlled human exposure, animal, or mode of action information) are limited or inconsistent; or b) animal toxico logical evidence from multiple studies from different labor atories that demonstrate effects, but limited or no human data are available. Evidence generally includes replicated and high

- quality studies by multiple investigators. Evidence is sufficient to conclude that there is a likely causal association with relevant pollut ant exposures. That is, an association has been observed be tween the pollutant and the outcome in studies in which chance, bias and confounding are minimized, but uncertainties remain.

For exa mple, field studies show a relationship, but suspected interacting factors cannot be controlled, and

other lines of evidence are limited or inconsistent. Generally, determination is based on multiple studies in multiple research groups.

Suggestive

of a causal relationship Evidence is suggestive of a causal relationship with
relevant blood or tissue Pb levels, but is limited because chance, bias and confounding cannot be ruled out. For example, at least one high

- quality epidemiologic study

shows an association with a given health outcome but the

results of other studies are inconsistent. Evidence is suggestive of a causal relationship with relevant pollutant exposures, but chance, bias and confounding cannot be ruled out. For example, at least

one hi gh

- quality study shows an effect, but the results of

other studies are inconsistent.

Inadequate

to infer a

causal relationship Evidence is inadequate to determine that a causal relationship exists with relevant blood or tissue Pb levels.

The available studies are of insufficient quantity, quality, consistency or statistical power to permit a conclu sion regarding the presence or absence of an effect. The available studies are of insufficient quality, consistency or statistical power to permit a conclusi on regarding the presence or absence of an effect.

Not likely to

be a causal relationship Evidence is suggestive of no causal relationship with relevant blood or tissue Pb levels. Several adequate studies, covering the full range of levels of exposure that human beings are known to encounter and considering susceptible populations, are mutually consistent in not showing an effect at any level of exposure. Several adequate studies, examining relationships with relevant exposures, are consistent in failing to show an effect at any level of exposure.

In drawing judgments regarding causality for the criteria air pollutants, EPA typically focuses 

### 1

on evidence of effects at relevant pollutant exposures. For making causality judgments for Pb health 

### 2

effects, the focus is on evidence of exposure or body burde n as indicated by relevant (within one 

### 3

order of magnitude) blood or tissue Pb levels of the current U.S. population (median blood Pb level 

### 4May 20 11 1

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– DO NOT CITE OR QUOTE = 1.3; 95 th percentile = 4.1; 99 th percentile = 7.2)

. Studies of the efficacy of chelation therapy in Pb



### 1

poisoned chi ldren and toxicological studies in which Pb levels were sufficiently high to induce an 

### 2

overtly toxic response in the animals (e.g.

, mortality) were specifically excluded. Studies of workers 

### 3

exposed to Pb in occupational settings were generally considered i n the causal determinations. 

### 4

Building upon the determination of causality are questions relevant to quantifying health or 

### 5

environmental risks based on our understanding of the quantitative relationships between pollutant 

### 6

exposures or biomarkers and health or welfare effects. While the causality determination is based 

### 7

primarily on evaluation of health or environmental effects evidence, EPA also evaluates evidence 

### 8

related to the doses or biomarker levels at which effects are observed. Considerations relevant to 

### 9

evaluation of quantitative relationships for health and environmental effects are summarized below. 

### 10



## 1.6.5.1. Effects on Human Populations

Once a determination is made regarding the causal relationship between the pollutant and 

### 11

outcome category, i mportant questio ns regarding quantitative relationships include: 

### 12

 What is the concentration

- response , exposure

- response, or dose

- response relationship in 

### 13

the human population? 

### 14

 What is the interrelationship between incidence and severity of effect? 

### 15

 What exposure conditions (dose or exposure, duration and pattern) are important? 

### 16

 What populations appear to be differentially affected (i.e., more susceptible to effects)? 

### 17

To address these questions, the entirety of policy

- relevant quantitative evidence is evaluated to 

### 18

best quantify those concentration

- response relationships that exist. For Pb, evaluation of blood or 

### 19

tissue Pb concentrations at which effects were observed for exposed populations, including 

### 20

potentially susceptible po pulations , has been an important element of this process. The integration of 

### 21

evidence resulted in identification of a study or set of studies that best approximated the 

### 22

concentration

- response relationships between blood Pb and various health outcomes, give n the 

### 23

current state of knowledge and the uncertainties that surrounded these estimates. To accomplish this, 

### 24

evidence is considered from multiple and diverse types of studies. To the extent available, the ISA 

### 25

evaluates results from across epidemiologic stud ies that use various methods to evaluate the form of 

### 26

relationships between blood or tissue Pb concentrations and health outcomes and draws conclusions 

### 27

on the most well

- supported shape of these relationships. Animal data may also inform evaluation of 

### 28

concen tration

- response relationships, particularly relative to MOAs and characteristics of susceptible 

### 29

populations. Chapter 2 presents the integrated findings informative for evaluation of population 

### 30

risks. 

### 31May 20 11 1

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– DO NOT CITE OR QUOTE An important consideration in characterizing the public health impacts associated with 

### 1

exposure to a pollutant is whether the concentration

- response relationship is linear across the full 

### 2

concentration range encountered or if nonlinear relationships exist along any part of this range. In 

### 3

general, t he shape of the concentration

- response curve varies, depending on the type of health 

### 4

outcome, underlying MOA and dose. At the human population level, however, various sources of 

### 5

variability and uncertainty, such as t he low data density at the lowest blood Pb levels , p ossible 

### 6

influence of exposure measurement error, and individual differences in susceptibility to Pb health 

### 7

effects, tend to smooth and “ linearize ” the concentration

- response function. In addition, many 

### 8

chemicals and agents may act by perturbing naturally o ccurring background processes that lead to 

### 9

disease, which also linearizes population concentration

- response relationships ( Clewell & Crump, 

### 10

2005 ; Crump et al., 1976 ; Hoel, 1980 ) . These attributes of population dose

- respon se may explain 

### 11

why the available human data at ambient concentrations for some environmental pollutants (e.g., Pb, 

### 12

PM, O 3 , environmental tobacco smoke [ETS], radiation) do not exhibit evident thresholds for cancer 

### 13

or noncancer health effects, even though l ikely mechanisms include nonlinear processes for some 

### 14

key events. These attributes of human population dose

- response relationships have been extensively 

### 15

discussed in the broader epidemiologic literature ( Rothman & Greenland, 1998 )

. Of particular 

### 16

interest for Pb is the shape of the concentration

- response curve at the low end (<10 μg/dL) of 

### 17

current blood Pb concentrations observed in the U.S. population. 

### 18

Publication bias is a source of uncertainty regarding the magnitude of health risk estimates. It 

### 19

is well understood that studies reporting non

- null findings are more likely to be published than 

### 20

reports of null findings, and publicatio n bias can also result in overestimation of effect estimate sizes 

### 21

( Ioannidis, 2008 ) . For example, effect estimates from single

- city epidemiologic studies have been 

### 22

found to be generally larger than those from multicity studies ( Anderson et al., 2005 )

. 

### 23

Finally, identification of the susceptible population groups contributes to an understanding of 

### 24

the public health impact of pollutant exposures. In this ISA, the term “ susceptible population ” will 

### 25

be used as an overarching concept to encompass populations variously described as susceptible, 

### 26

vulnerable, or sensitive. “ Susceptible populations ” is defined here as those populations that have a 

### 27

greater likelihood of experiencing health effects related to exposure to an air pollutant (e.g., Pb) due 

### 28

to a variety of factors including but not limited to: genetic or developmental factors, race, gender, 

### 29

lifestage, lifestyle (e.g., smoking status and nutrition) or preexisting disease; as well a s population



### 30

level factors that can increase an individual ’ s exposure to an air pollutant (e.g., Pb) such as 

### 31

socioeconomic status [SES], which encompasses reduced access to health care, low educational 

### 32

attainment, residential location, and other factors. E pidemiologic studies can help identify 

### 33

susceptible populations by evaluating health responses in the study population. Examples include 

### 34

stratified analyses for subsets of the population under study or testing for interactions or effect 

### 35

modification by fact ors such as gender, age group, or health status. Experimental studies using 

### 36May 20 11 1

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– DO NOT CITE OR QUOTE animal models of susceptibility or disease can also inform the extent to which health risks are likely 

### 1

greater in specific population groups. Further discussion of these groups is presented in Chapter 6

. 

### 2



## 1.6.5.2. Effects on Ecosystems or Public Welfare

Key questions for understanding the quantitative relationships between exposure (or 

### 3

concentration or deposition) to a pollutant and risk to ecosystems or the public welfare include: 

### 4

 What elem ents of the ecosystem (e.g., types, regions, taxonomic groups, populations, 

### 5

functions, etc.) appear to be affected, or are more sensitive to effects? 

### 6

 Under what exposure conditions (amount deposited or concentration, duration and 

### 7

pattern) are effects obser ved? 

### 8

 What is the shape of the concentration

- response or exposure

- response relationship? 

### 9

Evaluations of causality generally consider the probability of quantitative changes in 

### 10

ecological and welfare effects in response to exposure. A challenge to the quan tification of exposure



### 11

response relationships for ecological effects is the great regional and local variability in ecosystems. 

### 12

Thus, exposure

- response relationships are often determined for a specific ecological system and 

### 13

scale, rather than at the nation al or even regional scale. Quantitative relationships therefore are 

### 14

available site by site. For example, an ecological response to deposition of a given pollutant can 

### 15

differ greatly between ecosystems. Where results from greenhouse or animal ecotoxicologic al 

### 16

studies are available, they may be used to aid in characterizing exposure

- response relations, 

### 17

particularly relative to mechanisms of action, and characteristics of sensitive biota. 

### 18



## 1.6.6. Concepts in Evaluating Adversity of Health Effects

In evaluating the he alth evidence, a number of factors can be considered in determining the 

### 19

extent to which health effects are “ adverse ” for health outcomes such as changes in lung function or 

### 20

in cardiovascular health measures. Some health outcome events, such as hospitalizat ion for 

### 21

respiratory or cardiovascular diseases, are clearly considered adverse; what is more difficult is 

### 22

determining the extent of change in the more subtle health measures that is adverse. What constitutes 

### 23

an adverse health effect may vary between popula tions. Some changes in healthy individuals may 

### 24

not be considered adverse while those of a similar type and magnitude are potentially adverse in 

### 25

more susceptible individuals. 

### 26

For example, the extent to which changes in lung function are adverse has been di scussed by 

### 27

the American Thoracic Society (ATS) in an official statement titled What Constitutes an Adverse 

### 28

Health Effect of Air Pollution? ( 2000 ) . This statement updated the guid ance for defining adverse 

### 29

respiratory health effects that had been published 15 years earlier ( ATS, 1985 ) , taking into account 

### 30May 20 11 1

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– DO NOT CITE OR QUOTE new investigative approaches used to identify the effects of air pollution and reflecting concern for 

### 1

impacts of air pollution on specific susceptible groups. In the 2000 update, there was an increased 

### 2

focus on quality of life measures as indicators of adversity and a more specific consideration of 

### 3

population risk. Exposure to air pollution that incre ases the risk of an adverse effect to the entire 

### 4

population is viewed as adverse, even though it may not increase the risk of any identifiable 

### 5

individual to an unacceptable level. For example, a population of asthmatics could have a 

### 6

distribution of lung fu nction such that no identifiable individual has a level associated with 

### 7

significant impairment. Exposure to air pollution could shift the distribution such that no identifiable 

### 8

individual experiences clinically relevant effects. This shift toward decreased lung function, 

### 9

however, would be considered adverse because individuals within the population would have 

### 10

diminished reserve function and therefore would be at increased risk to further environmental insult. 

### 11



# 1.7. Summary

This draft ISA is a concise evaluation and synthesis of the most policy

- relevant science for 

### 12

reviewing the NAAQS for Pb, and it is the chief means for communicating the critical science 

### 13

judgments relevant to that NAAQS review. It reviews the most policy

- relevan t evidence from 

### 14

atmospheric science, exposure, and health and environmental effects studies and includes 

### 15

mechanistic evidence from basic biological science. A framework for making critical judgments 

### 16

concerning causality was presented in this chapter. It re lies on a widely accepted set of principles and 

### 17

standardized language to express evaluation of the evidence. This approach can bring rigor and 

### 18

clarity to current and future assessments. Once complete, the ISA should assist EPA and others, now 

### 19

and in the fu ture, to accurately represent what is presently known and what remains unknown 

### 20

concerning the effects of Pb on human health and public welfare. 

### 21May 20 11 1

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– DO NOT CITE OR QUOTE 

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Ioannidis, J. P. A. (2008). Why most discovered true associations are inflated. Epidemiology, 19 (5), 640

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NAPAP. (National Acid Precipitation Assessment Program). (1991). The experience and legacy of NAPAP: Report of the

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progress . Washington, DC: National Academy Press.

Rothman, K. J., & Greenland, S. (1998). Modern epidemiology (2nd ed.). Philad elphia, PA: Lippincott

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